Beyond Carbapenemases: Chromosomal Resistance Mechanisms and Carbapenemase Type Determine Susceptibility to Novel β-Lactam/β-Lactamase Inhibitor Combinations and Cefiderocol in Carbapenem-Resistant Pseudomonas aeruginosa from China

Background: β-lactam/β-lactamase inhibitor combinations (BL/BLIs) and siderophore cephalosporin serve as critical polymyxin alternatives for carbapenem-resistant Pseudomonas aeruginosa (CRPA). However, systematic multicenter clinical data from China and the resistance mechanisms underlying non-susceptibility to these agents remain poorly defined. Methods: We collected 442 CRPA isolates from 10 hospitals across eight Chinese provinces (2017–2025), determined minimum inhibitory concentrations (MICs) for cefiderocol (FDC), ceftazidime–avibactam (CZA), imipenem–relebactam (IMR), and ceftolozane–tazobactam (CT) through broth microdilution, and performed whole-genome sequencing. Resistance genes, virulence factors, and sequence types (STs) were identified. A chromosomal co-selection score (eight non-mobile resistance genes) was constructed. Multivariable regression and receiver operating characteristic (ROC) analysis identified predictors of non-susceptibility. Results: Carbapenemase genes were detected in only 33 isolates (7.5%): metallo β lactamase (MBL) genes in 28, blaKPC-2 in 2, and blaGES 5/14 in 3; the ST463 clone was absent. MBL producers were resistant to CZA, IMR, and CT (0–4% susceptible) but 100% susceptible to FDC. KPC 2 and GES producers were CZA-susceptible (100%) but IMR- and CT-resistant. Among 127 CZA non-susceptible isolates, 99 (78%) lacked carbapenemase genes; ST270 (from a single center) accounted for 64.6% of these. The chromosomal score independently predicted MIC (ρ: CT 0.64, FDC 0.59, IMR 0.50, CZA 0.25—largely attributable to ST270; all p < 0.001). ExoU positive isolates had lower MICs (FDC median 0.12 vs. 0.25 mg/L, p < 0.001). FDC remained active against 97.3% of all isolates and 100% of carbapenemase-positive ones. Genotype-based prediction yielded area under the ROC curve (AUC) values of 0.86 (CT) and 0.80 (CZA). Conclusions: Mechanisms other than acquired carbapenemases—consistent with chromosomal determinants—accounted for most non-susceptibility in this predominantly northern Chinese respiratory tract CRPA collection. Carbapenemase types determine distinct drug susceptibility patterns. Routine carbapenemase detection fails to identify most CZA-resistant strains. FDC retained the broadest in vitro activity and is a reliable therapeutic option pending clinical outcome data, and ST270-associated resistance deserves continuous surveillance.